Dehydration of Lipid Membranes Drives Redistribution of Cholesterol Between Lateral Domains.

Cholesterol-rich lipid rafts are found to facilitate membrane fusion, central to processes like viral entry, fertilization, and neurotransmitter release. While the fusion process involves local, transient membrane dehydration, the impact of reduced hydration on cholesterol's structural organization in biological membranes remains unclear. Here, we employ confocal fluorescence microscopy and atomistic molecular dynamics simulations to investigate cholesterol behavior in phase-separated lipid bilayers under controlled hydration. We unveiled that dehydration prompts cholesterol release from raft-like domains into the surrounding fluid phase. Unsaturated phospholipids undergo more significant dehydration-induced structural changes and lose more hydrogen bonds with water than sphingomyelin. The results suggest that cholesterol redistribution is driven by the equalization of biophysical properties between phases and the need to satisfy lipid hydrogen bonds. This underscores the role of cholesterol-phospholipid-water interplay in governing cholesterol affinity for a specific lipid type, providing a new perspective on the regulatory role of cell membrane heterogeneity during membrane fusion.

Identification of multiple plasma lipids as diagnostic biomarkers of hypercholesterolemia and the underlying mechanisms based on pseudo-targeted lipidomics.

RATIONALE: Hypercholesterolemia is an important risk factor for cardiovascular diseases and death. This study performed pseudo-targeted lipidomics to identify differentially expressed plasma lipids in hypercholesterolemia, to provide a scientific basis for the diagnosis and pathogenesis of hypercholesterolemia. METHODS: Pseudo-targeted lipidomic analyses of plasma lipids from 20 patients with hypercholesterolemia and 20 normal control subjects were performed using liquid chromatography-mass spectrometry. Differentially expressed lipids were identified by principal component analysis and orthogonal partial least squares discriminant analysis. Receiver operating characteristic curves were used to identify differentially expressed lipids with high diagnostic value. The Kyoto Encyclopedia of Genes and Genomes pathway database was used to identify enriched metabolic pathways. RESULTS: We identified 13 differentially expressed lipids in hypercholesterolemia using variable importance of projection > 1 and p < 0.05 as threshold parameters. The levels of eight sphingomyelins and cholesterol sulfate were higher and those of three triacylglycerols and lysophosphatidylcholine were reduced in hypercholesterolemia. Seven differentially expressed plasma lipids showed high diagnostic value for hypercholesterolemia. Functional enrichment analyses showed that pathways related to necroptosis, sphingolipid signaling, sphingolipid metabolism, and steroid hormone biosynthesis were enriched. CONCLUSIONS: This pseudo-targeted lipidomics study demonstrated that multiple sphingomyelins and cholesterol sulfate were differentially expressed in the plasma of patients with hypercholesterolemia. We also identified seven plasma lipids, including six sphingomyelins and cholesterol sulfate, with high diagnostic value.

Metabolomics of Multiple Sclerosis Lesions Demonstrates Lipid Changes Linked to Alterations in Transcriptomics-Based Cellular Profiles.

BACKGROUND AND OBJECTIVES: People with multiple sclerosis (MS) have a dysregulated circulating metabolome, but the metabolome of MS brain lesions has not been studied. The aims of this study were to identify differences in the brain tissue metabolome in MS compared with controls and to assess its association with the cellular profile of corresponding tissue. METHODS: MS tissues included samples from the edge and core of chronic active or inactive lesions and periplaque white matter (WM). Control specimens were obtained from normal WM. Metabolomic analysis was performed using mass-spectrometry coupled with liquid/gas chromatography and subsequently integrated with single-nucleus RNA-sequencing data by correlating metabolite abundances with relative cell counts, as well as individual genes using Multiomics Factor Analysis (MOFA). RESULTS: Seventeen samples from 5 people with secondary progressive MS and 8 samples from 6 controls underwent metabolomic profiling identifying 783 metabolites. MS lesions had higher levels of sphingosines (false discovery rate-adjusted p-value[q] = 2.88E-05) and sphingomyelins and ceramides (q = 2.15E-07), but lower nucleotide (q = 0.05), energy (q = 0.001), lysophospholipid (q = 1.86E-07), and monoacylglycerol (q = 0.04) metabolite levels compared with control WM. Periplaque WM had elevated sphingomyelins and ceramides (q = 0.05) and decreased energy metabolites (q = 0.01) and lysophospholipids (q = 0.05) compared with control WM. Sphingolipids and membrane lipid metabolites were positively correlated with astrocyte and immune cell abundances and negatively correlated with oligodendrocytes. On the other hand, long-chain fatty acid, endocannabinoid, and monoacylglycerol pathways were negatively correlated with astrocyte and immune cell populations and positively correlated with oligodendrocytes. MOFA demonstrated associations between differentially expressed metabolites and genes involved in myelination and lipid biosynthesis. DISCUSSION: MS lesions and perilesional WM demonstrated a significantly altered metabolome compared with control WM. Many of the altered metabolites were associated with altered cellular composition and gene expression, indicating an important role of lipid metabolism in chronic neuroinflammation in MS.

Human milk sphingomyelin: Function, metabolism, composition and mimicking.

Human milk, which contains various nutrients, is the "gold standard" for infant nutrition. Healthy human milk meets all the nutritional needs of early infant development. Polar lipids mainly exist in the milk fat globule membrane, accounting for approximately 1-2% of human milk lipids; sphingomyelin (SM) accounts for approximately 21-24% of polar lipids. SM plays an important role in promoting the development of the brain and nervous system, regulating intestinal flora, and improving skin barriers. Though SM could be synthesized de novo, SM nutrition from dietary is also important for infants. The content and composition of SM in human milk has been reported, however, the molecular mechanisms of nutritional functions of SM for infants required further research. This review summarizes the functional mechanisms, metabolic pathways, and compositional, influencing factors, and mimicking of SM in human milk, and highlights the challenges of improving maternal and infant early/long-term nutrition.

Screening by Q Exactive liquid chromatography/tandem mass spectrometry identified Choline, 25-hydroxyvitamin D2, and SM(d18:0/16:1(9Z) (OH)) as biomarkers for high-grade serous ovarian cancer.

High-grade serous ovarian cancer (HGSOC) has a high death rate and poor prognosis. The main causes of poor prognosis are asymptomatic early disease, no effective screening method at present, and advanced disease. Changes in cellular metabolism are characteristic of cancer, and plasma metabolome analysis can be used to identify biomarkers. In this study, we used Q Exactive liquid chromatography tandem mass spectrometry (LC-MS/MS, QE) to compare the differentiation between plasma samples (22 HGSOC samples and 22 normal samples). In total, we detected 124 metabolites, and an orthogonal partial least-squares-discriminant analysis (OPLS-DA) model was useful to distinguish HGSOC patients from healthy controls. Choline, 25-hydroxyvitamin D2, and sphingomyelin (d18:0/16:1(9Z) (OH))/SM(d18:0/16:1(9Z) (OH)) showed significantly differential plasma levels in HGSOC patients under the conditions of variable importance in projection (VIP) > 1, p < 0.05 using Student's t-test, and fold change (FC)  ≥ 1.5 or ≤ 0.667. Metabolic pathway analysis can provide valuable information to enhance the understanding of the underlying pathophysiology of HGSOC. In conclusion, the Q Exactive LC/MS/MS method validation-based plasma metabolomics approach may have potential as a convenient screening method for HGSOC and may be a method to monitor tumor recurrence in patients with HGSOC after surgery SIGNIFICANCE: High-grade serous ovarian cancer (HGSOC) has a high death rate and poor prognosis. The main causes of poor prognosis are asymptomatic early disease, no effective screening method at present, and advanced disease. Changes in cellular metabolism are characteristic of cancer, and plasma metabolome analysis can be used to identify biomarkers. In this study, we used Q Exactive liquid chromatography tandem mass spectrometry (LC-MS/MS, QE) to compare the differentiation between plasma samples (20 HGSOC samples and 20 normal samples). In total, we detected 124 metabolites, and an orthogonal partial least-squares-discriminant analysis (OPLS-DA) model was useful to distinguish HGSOC patients from healthy controls. Choline, 25-hydroxyvitamin D2, and sphingomyelin (d18:0/16:1(9Z) (OH))/SM(d18:0/16:1(9Z) (OH)) showed significantly differential plasma levels in HGSOC patients under the conditions of variable importance in projection (VIP) > 1, p < 0.05 using Student's t-test, and fold change (FC) ≥ 1.5 or ≤ 0.667. Metabolic pathway analysis can provide valuable information to enhance the understanding of the underlying pathophysiology of HGSOC. In conclusion, the Q Exactive LC/MS/MS method validation-based plasma metabolomics approach may have potential as a convenient screening method for HGSOC and may be a method to monitor tumor recurrence in patients with HGSOC after surgery.

Dietary habits and plasma lipid concentrations in a general Japanese population.

INTRODUCTION: Accumulating data on the associations between food consumption and lipid composition in the body is essential for understanding the effects of dietary habits on health. OBJECTIVES: As part of omics research in the Tohoku Medical Megabank Community-Based Cohort Study, this study sought to reveal the dietary impact on plasma lipid concentration in a Japanese population. METHODS: We conducted a correlation analysis of food consumption and plasma lipid concentrations measured using mass spectrometry, for 4032 participants in Miyagi Prefecture, Japan. RESULTS: Our analysis revealed 83 marked correlations between six food categories and the concentrations of plasma lipids in nine subclasses. Previously reported associations, including those between seafood consumption and omega-3 fatty acids, were validated, while those between dairy product consumption and odd-carbon-number fatty acids (odd-FAs) were validated for the first time in an Asian population. Further analysis suggested that dairy product consumption is associated with odd-FAs via sphingomyelin (SM), which suggests that SM is a carrier of odd-FAs. These results are important for understanding odd-FA metabolism with regards to dairy product consumption. CONCLUSION: This study provides insight into the dietary impact on plasma lipid concentration in a Japanese population.

Plasma metabolomic profile in orthostatic intolerance children with high levels of plasma homocysteine.

BACKGROUND: Orthostatic intolerance, which includes vasovagal syncope and postural orthostatic tachycardia syndrome, is common in children and adolescents. Elevated plasma homocysteine levels might participate in the pathogenesis of orthostatic intolerance. This study was designed to analyze the plasma metabolomic profile in orthostatic intolerance children with high levels of plasma homocysteine. METHODS: Plasma samples from 34 orthostatic intolerance children with a plasma homocysteine concentration > 9 µmol/L and 10 healthy children were subjected to ultra-high-pressure liquid chromatography and quadrupole-time-of-flight mass spectrometry analysis. RESULTS: A total of 875 metabolites were identified, 105 of which were significantly differential metabolites. Choline, 1-stearoyl-2-linoleoyl-sn-glycero-3-phosphocholine, 1-(1Z-octadecenyl)-2-(4Z,7Z,10Z,13Z,16Z,19Z-docosahexaenoyl)-sn-glycero-3-phosphocholine, histidine, isocitric acid, and DL-glutamic acid and its downstream metabolites were upregulated, whereas 1-palmitoyl-sn-glycero-3-phosphocholine, 1-stearoyl-sn-glycerol 3-phosphocholine, sphingomyelin (d18:1/18:0), betaine aldehyde, hydroxyproline, and gamma-aminobutyric acid were downregulated in the orthostatic intolerance group compared with the control group. All these metabolites were related to choline and glutamate. Heatmap analysis demonstrated a common metabolic pattern of higher choline, 1-stearoyl-2-linoleoyl-sn-glycero-3-phosphocholine, and DL-glutamic acid, and lower sphingomyelin (d18:1/18:0), 1-stearoyl-sn-glycerol 3-phosphocholine, and 1-palmitoyl-sn-glycero-3-phosphocholine in patients with certain notable metabolic changes (the special group) than in the other patients (the common group). The maximum upright heart rate, the change in heart rate from the supine to the upright position, and the rate of change in heart rate from the supine to the upright position of vasovagal syncope patients were significantly higher in the special group than in the common group (P < 0.05). Choline, 1-stearoyl-2-linoleoyl-sn-glycero-3-phosphocholine, and DL-glutamic acid were positively correlated with the rate of change in heart rate from the supine to the upright position in vasovagal syncope patients (P < 0.05). CONCLUSIONS: The levels of choline-related metabolites and glutamate-related metabolites changed significantly in orthostatic intolerance children with high levels of plasma homocysteine, and these changes were associated with the severity of illness. These results provided new light on the pathogenesis of orthostatic intolerance.

Sphingolipid-Induced Bone Regulation and Its Emerging Role in Dysfunction Due to Disease and Infection.

The human skeleton is a metabolically active system that is constantly regenerating via the tightly regulated and highly coordinated processes of bone resorption and formation. Emerging evidence reveals fascinating new insights into the role of sphingolipids, including sphingomyelin, sphingosine, ceramide, and sphingosine-1-phosphate, in bone homeostasis. Sphingolipids are a major class of highly bioactive lipids able to activate distinct protein targets including, lipases, phosphatases, and kinases, thereby conferring distinct cellular functions beyond energy metabolism. Lipids are known to contribute to the progression of chronic inflammation, and notably, an increase in bone marrow adiposity parallel to elevated bone loss is observed in most pathological bone conditions, including aging, rheumatoid arthritis, osteoarthritis, and osteomyelitis. Of the numerous classes of lipids that form, sphingolipids are considered among the most deleterious. This review highlights the important primary role of sphingolipids in bone homeostasis and how dysregulation of these bioactive metabolites appears central to many chronic bone-related diseases. Further, their contribution to the invasion, virulence, and colonization of both viral and bacterial host cell infections is also discussed. Many unmet clinical needs remain, and data to date suggest the future use of sphingolipid-targeted therapy to regulate bone dysfunction due to a variety of diseases or infection are highly promising. However, deciphering the biochemical and molecular mechanisms of this diverse and extremely complex sphingolipidome, both in terms of bone health and disease, is considered the next frontier in the field.

Cholesterol-modified sphingomyelin chimeric lipid bilayer for improved therapeutic delivery.

Cholesterol (Chol) fortifies packing and reduces fluidity and permeability of the lipid bilayer in vesicles (liposomes)-mediated drug delivery. However, under the physiological environment, Chol is rapidly extracted from the lipid bilayer by biomembranes, which jeopardizes membrane stability and results in premature leakage for delivered payloads, yielding suboptimal clinic efficacy. Herein, we report a Chol-modified sphingomyelin (SM) lipid bilayer via covalently conjugating Chol to SM (SM-Chol), which retains membrane condensing ability of Chol. Systemic structure activity relationship screening demonstrates that SM-Chol with a disulfide bond and longer linker outperforms other counterparts and conventional phospholipids/Chol mixture systems on blocking Chol transfer and payload leakage, increases maximum tolerated dose of vincristine while reducing systemic toxicities, improves pharmacokinetics and tumor delivery efficiency, and enhances antitumor efficacy in SU-DHL-4 diffuse large B-cell lymphoma xenograft model in female mice. Furthermore, SM-Chol improves therapeutic delivery of structurally diversified therapeutic agents (irinotecan, doxorubicin, dexamethasone) or siRNA targeting multi-drug resistant gene (p-glycoprotein) in late-stage metastatic orthotopic KPC-Luc pancreas cancer, 4T1-Luc2 triple negative breast cancer, lung inflammation, and CT26 colorectal cancer animal models in female mice compared to respective FDA-approved nanotherapeutics or lipid compositions. Thus, SM-Chol represents a promising platform for universal and improved drug delivery.

Development of an advanced liquid chromatography-tandem mass spectrometry measurement system for simultaneous sphingolipid analysis.

Mass spectrometry-based lipidomics approaches offer valuable tools for the detection and quantification of various lipid species, including sphingolipids. The present study aimed to develop a new method to simultaneously detect various sphingolipid species that applies to diverse biological samples. We developed and validated a measurement system by employing a single-column liquid chromatography-mass spectrometry system utilizing a normal-phase separation mode with positive ionization. The measurement system provided precision with a coefficient of variant below 20% for sphingolipids in all types of samples, and we observed good linearity in diluted serum samples. This system can measure the following sphingolipids: sphingosine 1-phosphate (S1P), sphingosine (Sph), dihydroS1P (dhS1P), dihydroSph (dhSph), ceramide 1-phosphate (Cer1P), hexosylceramide (HexCer), lactosylceramide (LacCer), dh-ceramide, deoxy-ceramide, deoxy-dh-ceramide, and sphingomyelin (SM). By measuring these sphingolipids in cell lysates where S1P lyase expression level was modulated, we could observe significant and dynamic modulations of sphingolipids in a comprehensive manner. Our newly established and validated measurement system can simultaneously measure many kinds of sphingolipids in biological samples. It holds great promise as a valuable tool for laboratory testing applications to detect overall modulations of sphingolipids, which have been proposed to be involved in pathogenesis processes in a series of elegant basic research studies.

Maternal serum amino acids and hydroxylated sphingomyelins at pregnancy are associated with anxiety symptoms during pregnancy and throughout the first year after delivery.

BACKGROUND: Studies suggest an interplay between maternal metabolome and mental health. OBJECTIVE: We investigated the association of maternal serum metabolome at pregnancy with anxiety scores during pregnancy and throughout the first year postpartum. METHODS: A prospective cohort of Brazilian women collected 119 serum metabolome at pregnancy (28-38 weeks) and anxiety scores measured by the State-Trait Anxiety Inventory (STAI) at pregnancy (n = 118), 1 (n = 83), 6 (n = 68), and 12 (n = 57) months postpartum. Targeted metabolomics quantified metabolites belonging to amino acids (AA), biogenic amines/amino acid-related compounds, acylcarnitines, lysophosphatidylcholines, diacyl phosphatidylcholines, alkyl:acyl phosphatidylcholines, non-hydroxylated and hydroxylated sphingomyelins [SM(OH)], and hexoses classes. Linear mixed-effect models were used to evaluate the association of metabolites and STAI scores. Hierarchical clustering and principal component analyses were employed to identify clusters and metabolites, which drove their main differences. Multiple comparison-adjusted p-values (q-value) ≤ 0.05 were considered significant. RESULTS: AA (ß = -1.44) and SM(OH) (ß = -1.49) classes showed an association with STAI scores trajectory (q-value = 0.047). Two clusters were identified based on these classes. Women in cluster 2 had decreased AA and SM(OH) concentrations and higher STAI scores (worse symptoms) trajectory (ß = 2.28; p-value = 0.041). Isoleucine, leucine, valine, SM(OH) 22:1, 22:2, and 24:1 drove the main differences between the clusters. LIMITATIONS: The target semiquantitative metabolome analysis and small sample size limited our conclusions. CONCLUSIONS: Our results suggest that AA and SM(OH) during pregnancy play a role in anxiety symptoms throughout the first year postpartum.

Differential effects of the lipidic and ionic microenvironment on NPP1's phosphohydrolase and phosphodiesterase activities.

Ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1) is an enzyme present in matrix vesicles (MV). NPP1 participates on the regulation of bone formation by producing pyrophosphate (PPi) from adenosine triphosphate (ATP). Here, we have used liposomes bearing dipalmitoylphosphatidylcholine (DPPC), sphingomyelin (SM), and cholesterol (Chol) harboring NPP1 to mimic the composition of MV lipid rafts to investigate ionic and lipidic influence on NPP1 activity and mineral propagation. Atomic force microscopy (AFM) revealed that DPPC-liposomes had spherical and smooth surface. The presence of SM and Chol elicited rough and smooth surface, respectively. NPP1 insertion produced protrusions in all the liposome surface. Maximum phosphodiesterase activity emerged at 0.082 M ionic strength, whereas maximum phosphomonohydrolase activity arose at low ionic strength. Phosphoserine-Calcium Phosphate Complex (PS-CPLX) and amorphous calcium-phosphate (ACP) induced mineral propagation in DPPC- and DPPC:SM-liposomes and in DPPC:Chol-liposomes, respectively. Mineral characterization revealed the presence of bands assigned to HAp in the mineral propagated by NPP1 harbored in DPPC-liposomes without nucleators or in DPPC:Chol-liposomes with ACP nucleators. These data show that studying how the ionic and lipidic environment affects NPP1 properties is important, especially for HAp obtained under controlled conditions in vitro.

Metabolomic associations of impaired awareness of hypoglycaemia in type 1 diabetes.

This study investigates impaired awareness of hypoglycaemia (IAH), a complication of insulin therapy affecting 20-40% of individuals with type 1 diabetes. The exact pathophysiology is unclear, therefore we sought to identify metabolic signatures in IAH to elucidate potential pathophysiological pathways. Plasma samples from 578 individuals of the Dutch type 1 diabetes biomarker cohort, 67 with IAH and 108 without IAH (NAH) were analysed using the targeted metabolomics Biocrates AbsoluteIDQ p180 assay. Eleven metabolites were significantly associated with IAH. Genome-wide association studies of these 11 metabolites identified significant single nucleotide polymorphisms (SNPs) in C22:1-OH and phosphatidylcholine diacyl C36:6. After adjusting for the SNPs, 11 sphingomyelins and phosphatidylcholines were significantly higher in the IAH group in comparison to NAH. These metabolites are important components of the cell membrane and have been implicated to play a role in cell signalling in diabetes. These findings demonstrate the potential role of phosphatidylcholine and sphingomyelins in IAH.

ReTimeML: a retention time predictor that supports the LC-MS/MS analysis of sphingolipids.

The analysis of ceramide (Cer) and sphingomyelin (SM) lipid species using liquid chromatography-tandem mass spectrometry (LC-MS/MS) continues to present challenges as their precursor mass and fragmentation can correspond to multiple molecular arrangements. To address this constraint, we developed ReTimeML, a freeware that automates the expected retention times (RTs) for Cer and SM lipid profiles from complex chromatograms. ReTimeML works on the principle that LC-MS/MS experiments have pre-determined RTs from internal standards, calibrators or quality controls used throughout the analysis. Employed as reference RTs, ReTimeML subsequently extrapolates the RTs of unknowns using its machine-learned regression library of mass-to-charge (m/z) versus RT profiles, which does not require model retraining for adaptability on different LC-MS/MS pipelines. We validated ReTimeML RT estimations for various Cer and SM structures across different biologicals, tissues and LC-MS/MS setups, exhibiting a mean variance between 0.23 and 2.43% compared to user annotations. ReTimeML also aided the disambiguation of SM identities from isobar distributions in paired serum-cerebrospinal fluid from healthy volunteers, allowing us to identify a series of non-canonical SMs associated between the two biofluids comprised of a polyunsaturated structure that confers increased stability against catabolic clearance.

Lithocholic acid-based oligomers as drug delivery candidates targeting model of lipid raft.

This study presents a new approach to designing a lithocholic acid functionalized oligomer (OLithocholicAA-X) that can be used as a drug carrier with additional, beneficial activity. Namely, this novel oligomer can incorporate an anti-cancer drug due to the application of an effective backbone as its component (lithocholic acid) alone is known to have anticancer activity. The oligomer was synthesized and characterized in detail by nuclear magnetic resonance, attenuated total reflectance Fourier-transform infrared spectroscopy, ultraviolet-visible spectroscopy, thermal analysis, and mass spectrometry analysis. We selected lipid rafts as potential drug carrier-membrane binding sites. In this respect, we investigated the effects of OLithocholicAA-X on model lipid raft of normal and altered composition, containing an increased amount of cholesterol (Chol) or sphingomyelin (SM), using Langmuir monolayers and liposomes. The surface topography of the studied monolayers was additionally investigated by atomic force microscopy (AFM). The obtained results showed that the investigated oligomer has affinity for a system that mimics a normal lipid raft (SM:Chol 2:1). On the other hand, for systems with an excess of SM or Chol, thermodynamically unfavorable fluidization of the films occurs. Moreover, AFM topographies showed that the amount of SM determines the bioavailability of the oligomer, causing fragmentation of its lattice.

Impact of manufacturing processes on glycerolipid and polar lipid composition and ultrastructure in infant formula.

The introduction of exogenous lipids in the production of infant formula induces significant alterations in milk lipid composition, content, and membrane structure, thus affecting the lipid digestion, absorption, and utilization. This study meticulously tracks these changes throughout the manufacturing process. Pasteurization has a significant effect on phosphatidylcholine and sphingomyelin in the outer membrane, decreasing their relative contents to total polar lipids from 12.52% and 17.34% to 7.72% and 12.59%, respectively. Subsequent processes, including bactericidal-concentration and spray-drying, demonstrate the thermal stability of sphingomyelin and ceramides, while glycerolipids with arachidonic acid/docosahexaenoic acid and glycerophospholipids, particularly phosphatidylethanolamine, diminish significantly. Polar lipids addition and freeze-drying technology significantly enhance the polar lipid content and improve microscopic morphology of infant formula. These findings reveal the diverse effects of technological processes on glycerolipid and polar lipid compositions, concentration, and ultrastructure in infant formulas, thus offering crucial insights for optimizing lipid content and structure within infant formula.

Lung molecular and histological changes in type 2 diabetic rats and its improvement by high-intensity interval training.

BACKGROUND: Type 2 diabetes (T2D) leads to serious respiratory problems. This study investigated the effectiveness of high-intensity interval training (HIIT) on T2D-induced lung injuries at histopathological and molecular levels. METHODS: Forty-eight male Wistar rats were randomly allocated into control (CTL), Diabetes (Db), exercise (Ex), and Diabetes + exercise (Db + Ex) groups. T2D was induced by a high-fat diet plus (35 mg/kg) of streptozotocin (STZ) administration. Rats in Ex and Db + Ex performed HIIT for eight weeks. Tumor necrosis factor-alpha (TNFα), Interleukin 10 (IL-10), BAX, Bcl2, Lecithin, Sphingomyelin (SPM) and Surfactant protein D (SPD) levels were measured in the bronchoalveolar lavage fluid (BALF) and malondialdehyde (MDA) and total antioxidant capacity (TAC) levels were measured in lung tissue. Lung histopathological alterations were assessed by using H&E and trichrome mason staining. RESULTS: Diabetes was significantly associated with imbalance in pro/anti-inflammatory, pro/anti-apoptosis and redox systems, and reduced the SPD, lecithin sphingomyelin and alveolar number. Performing HIIT by diabetic animals increased Bcl2 (P < 0.05) and IL10 (P < 0.01) levels as well as surfactants components and TAC (P < 0.05) but decreased fasting blood glucose (P < 0.001), TNFα (P < 0.05), BAX (P < 0.05) and BAX/Bcl2 (P < 0.001) levels as well as MDA (P < 0.01) and MDA/TAC (P < 0.01) compared to the diabetic group. Furthermore, lung injury and fibrosis scores were increased by T2D and recovered in presence of HIIT. CONCLUSION: These findings suggested that the attenuating effect of HIIT on diabetic lung injury mediated by reducing blood sugar, inflammation, oxidative stress, and apoptosis as well as improving pulmonary surfactants components.

The effect of membrane composition on the interaction between human CYP51 and its flavonoid inhibitor - luteolin 7,3'-disulfate.

Cytochromes P450 (CYP) are a family of membrane proteins involved in the production of endogenous molecules and the metabolism of xenobiotics. It is well-known that the composition of the membrane can influence the activity and orientation of CYP proteins. However, little is known about how membrane composition affects the ligand binding properties of CYP. In this study, we utilized surface plasmon resonance and fluorescence lifetime analysis to examine the impact of membrane micro-environment composition on the interaction between human microsomal CYP51 (CYP51A1) and its inhibitor, luteolin 7,3'-disulphate (LDS). We observed that membranes containing cholesterol or sphingomyelin exhibited the lowest apparent equilibrium dissociation constant for the CYP51A1-LDS complex. Additionally, the tendency for relation between kinetic parameters of the CYP51A1-LDS complex and membrane viscosity and overall charge was observed. These findings suggest that the specific composition of the membrane, particularly the presence of cholesterol and sphingomyelin, plays a vital role in regulating the interaction between CYP enzymes and their ligands.

Circulating palmitoyl sphingomyelin levels predict the 10-year increased risk of cardiovascular disease death in Chinese adults: findings from the Da Qing Diabetes Study.

BACKGROUND: Higher levels of palmitoyl sphingomyelin (PSM, synonymous with sphingomyelin 16:0) are associated with an increased risk of cardiovascular disease (CVD) in people with diabetes. Whether circulating PSM levels can practically predict the long-term risk of CVD and all-cause death remains unclear. This study aimed to investigate whether circulating PSM is a real predictor of CVD death in Chinese adults with or without diabetes. METHODS: A total of 286 and 219 individuals with and without diabetes, respectively, from the original Da Qing Diabetes Study were enrolled. Blood samples collected in 2009 were used as a baseline to assess circulating PSM levels. The outcomes of CVD and all-cause death were followed up from 2009 to 2020, and 178 participants died, including 87 deaths due to CVD. Cox proportional hazards regression was used to estimate HRs and their 95% CIs for the outcomes. RESULTS: Fractional polynomial regression analysis showed a linear association between baseline circulating PSM concentration (log-2 transformed) and the risk of all-cause and CVD death (p < 0.001), but not non-CVD death (p > 0.05), in all participants after adjustment for confounders. When the participants were stratified by PSM-tertile, the highest tertile, regardless of diabetes, had a higher incidence of CVD death (41.5 vs. 14.7 and 22.2 vs. 2.9 per 1000 person-years in patients with and without diabetes, respectively, all log-rank p < 0.01). Individuals with diabetes in the highest tertile group had a higher risk of CVD death than those in the lowest tertile (HR = 2.73; 95%CI, 1.20-6.22). CONCLUSIONS: Elevated PSM levels are significantly associated with a higher 10-year risk of CVD death, but not non-CVD death, in Chinese adults with diabetes. These findings suggest that PSM is a potentially useful long-term predictor of CVD death in individuals with diabetes.

Multi-Omics Analysis Reveals Sphingomyelin Accumulation, Glycerolipids Loss, and Disorders of Lipid Metabolism Regulated by Leucine Deprivation in the Liver of Mice.

SCOPE: Branched-chain amino acids, especially leucine, have been reported to play a role in regulating lipid metabolism. This study aims to examine the effects of leucine deprivation on hepatic lipid metabolism. METHODS AND RESULTS: C57BL/6 mice are fed with a chow diet (control group, n = 8) or a leucine-free diet (-Leu group, n = 8) for 7 days. Histology, lipidomics, targeted metabolomics, and transcriptomics are performed to analyze the liver tissue. Compared to control group, -Leu group exhibits a notably reduced liver weight, accompanied by hepatic injury, and disorders of lipid metabolism. The level of sphingomyelin (SM) is significantly increased in the liver of -Leu group, while the glycerolipids (GL) level is significantly decreased. The expression of sphingomyelin synthase 1 (SGMS1) is upregulated by leucine deprivation in a time-dependent manner, leading to hepatic SM accumulation. Moreover, leucine deprivation results in hepatic GL loss via suppressing fatty acid synthase (FASN) and acetyl-CoA carboxylase 1 (ACC1) expression. CONCLUSION: The findings demonstrate that leucine deprivation results in abnormal lipid metabolism in the liver, mainly manifested as SM accumulation and GL loss. These results provide insights into the role of leucine in regulating lipid metabolism.